Maternal smoking during pregnancy (MSDP) has been associated with numerous adverse neurobehavioral outcomes in offspring, including attentional deficits, impulsivity, and recently, risk for nicotine dependence. However, although critical to the development of novel treatment strategies, little research has examined neurobiological mechanisms underlying these associations in humans. Further, few studies have investigated the neurobehavioral effects of nicotine in human infants. Given links between stress, stress hormones and smoking, and evidence for cross-sensitization of neural pathways by stress and nicotine, one potential mechanism underlying the adverse offspring effects of prenatal smoking exposure is dysregulated offspring stress responses. In the proposed pilot study, we will conduct the first investigation of the unique effects of prenatal nicotine exposure on stress responses in human infant offspring. Specifically, we will compare adrenocortical stress reactivity in infants exposed and unexposed to MSDP. We will also examine the relationship between fetal cotinine levels and infant stress reactivity. Forty smoking and forty non-smoking mothers matched in age, alcohol use, and socio-economic status, will be recruited into the study after giving birth. Smoking status will be determined by interview and biochemical verification. Smoking exposed (40) and non-exposed (40) normal birth weight infants will be compared on their adrenocortical (salivary cortisol) responses to a psychological stressor, the NICU Network Neurobehavioral Scale (NNNS). We hypothesize that exposed infants will show attenuated cortisol reactivity to the neurobehavioral examination compared to non-exposed infants. Additionally, we will explore dose-response relationships between smoking exposure (infant cotinine) and cortisol reactivity to the NNNS. Results will elucidate the distinctive effects of smoking exposure in human offspring, and should provide pilot data for a program of research examining the effects of prenatal smoking exposure on HPA stress responses. Results may also lead to the identification of biobehavioral markers for high-risk infants and to novel and targeted treatment strategies to reverse deficits from smoking exposure.